PROJECT SUMMARY The most common onset of bipolar disorder (BD) is during late adolescence and early adulthood. While pharmacotherapy is effective for BD symptoms in adolescents and young adults (AYA), poor adherence occurs in more than 65% of AYAs and is associated with low rates of recovery, high rates of relapse and a 5.2 fold increase in suicide risk. Poor adherence is a critical yet modifiable risk factor of poor outcomes in AYAs with BD. AYAs are an ideal BD subgroup to target and test adherence interventions given the potential impact of enhanced adherence on social, educational and occupational goals during this critical developmental period which can lay the foundation for lifelong BD self-management skills. To date, there are no interventions that specifically target adherence in AYAs with BD. This R34 proposal, written in response to RFA-MH-18-706, Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions will modify and test in AYAs with BD, an effective customized adherence enhancement (CAE) intervention developed for adults with BD by the investigative team. CAE is a brief, practical adherence promotion intervention that is highly generalizable to real-word clinical settings. In adults, CAE improves adherence significantly more than a rigorous BD-specific educational control. The investigative team is based in two academic medical centers (Case Western Reserve University/CWRU and University of Cincinnati/UC) led by two NIH-funded PIs with complementary strengths. The proposed 3-phase project will identify relevant characteristics of AYAs and needed refinements to CAE (Phase 1) and standardize the intervention using iterative refinements based on patient feedback (Phase 2). Phases 1 and 2 will be completed over a 12-month time-period. In Phase 3 (months 13-36) we will test the feasibility, acceptability and preliminary efficacy of the adapted approach using a randomized controlled trial (RCT) design in a high-risk, high-need group: AYAs ages 16-21 with BD who are poorly adherent with prescribed BD medications. The overall hypothesis is that CAE for poorly adherent AYAs with BD (CAE-AYA) will be associated with improved adherence at 6-month follow-up compared to enhanced treatment as usual (ETAU). The primary outcome will be change from baseline in the Tablets Routine Questionnaire (TRQ) and electronic adherence monitoring (SimpleMed boxes). Secondary outcomes will evaluate change in psychiatric symptoms and health- related quality of life. Additional analysis will examine the posited mechanisms of adherence change in BD AYAs as it relates to the adherence barriers of inadequate bipolar knowledge, poor communication with clinicians and family, unstable medication routines and substance use/risky behaviors. If proven effective, the proposed trial will pave the way for a rigorous efficacy trial of CAE-AYA.